Abstract The long-term objective of this proposal is to gain insight into mechanisms of cell-mediated immunity and unresponsiveness to intracellular pathogens in humans. Leprosy provides an extraordinary model to investigate these immunoregulatory processes. First, the disease primarily affects skin and is therefore accessible for study, proving a unique opportunity for investigating the immune response at the site of infection. Secondly, the disease represents a spectrum, in which the clinical manifestations correlate with the immune response to the pathogen. In particular, patients with the resistant tuberculoid form (T-Lep) express type 1 cytokines in lesions; whereas patients with progressive lepromatous form (L-Lep) manifest type 2 cytokines in lesions. Our progress {3942} and preliminary data indicate that i) disease lesion transcriptome analysis provides a new level of insight into immunologic mechanisms that contribute to host defense in humans; ii) TCR V6 T cell clones derived from T-lep patients are activated by a bacterial lipoglycoprotein (LprG); and iii) foam cells in L-lep lesions are M that contain host-derived oxidized phospholipids, a major component of mildly oxidized low density lipoprotein (LDL). We hypothesize that the outcome of the host response to M. leprae is determined by the nature of the innate and adaptive immune response in lesions. We now propose to: 1) elucidate the site of disease-host gene expression profiles associated with resistance versus susceptibility in the human immune response to an intracellular pathogen, 2) elucidate the mechanism by which T-cell recognition of a major microbial antigen, LprG contributes to host defense at the site of disease in leprosy; and, 3) investigate the mechanism by which host-derived lipids accumulate in macrophages in leprosy lesions. The studies we propose are intended to provide a comprehensive analysis of the immune response in leprosy, comparing host responses in patients that are resistant to infection vs. susceptible to progressive disease. We anticipate that such studies will provide new insights into mechanisms of immunoregulation in humans, and, we would hope, would provide the ability to predict disease outcome and also lead to the development of new immunomodulatory treatments for a variety of human infectious diseases.